The invention described herein relates to a chemical process for the stereoselective synthesis of R-(xe2x88x92)-carnitine.
As is known, carnitine contains an asymmetry centre and can therefore exist in the form of two enantiomorphs, designated R-(xe2x88x92)-carnitine and S-(+)-carnitine, respectively. Of these, only R-(xe2x88x92)-carnitine is present in living organisms where it acts as a carrier for the transport of fatty acids across the mitochondrial membranes. Whereas R-(xe2x88x92)-carnitine is the physiologically active enantiomorph, for some years the R,S racemate has been used as a therapeutic agent. It has had to be acknowledged, however, that S-(+)-carnitine is a competitive inhibitor of carnitine acetyltransferase and can lower the levels of R-(xe2x88x92)-carnitine in the myocardium and in skeletal muscle.
It is therefore essential that only R-(xe2x88x92)-carnitine be administered to patients undergoing haemodialysis treatment or those under treatment for cardiac or lipid metabolism disorders.
The same principle applies to the therapeutic use of acylated derivatives of carnitine for the treatment of disorders of cerebral metabolism, peripheral neuropathies, peripheral arteriopathies, etc., for which acetyl R-(xe2x88x92)-carnitine and propionyl R-(xe2x88x92)-carnitine are used, obtained by acetylation of R-(xe2x88x92)-carnitine.
Various chemical processes have been proposed for the production of carnitine on an industrial scale. These processes are generally non-stereospecific and therefore lead to racemic mixtures of R and S enantiomorphs. Consequently, resolution methods must be used to separate the constituent enantiomorphs of the racemate. Typically, the R,S racemic mixture is reacted with an optically active acid, selected, for example, from D-tartaric acid or D-camphorsulfonic acid, obtaining two diastereoisomers that can be separated from each other. In the classic process described in U.S. Pat. No. 4,254,053, D-camphoric acid is used as the resolvent of a racemic mixture of R,S carnitinamide, obtaining S-(+)-carnitine as the waste product, while the R-(xe2x88x92)-carnitinamide is hydrolysed to R-(xe2x88x92)-carnitine.
These resolution processes are therefore complex and expensive and, in any case, lead to the production of both R-(xe2x88x92)-carnitine and an equal amount of S-(+)-carnitine or of a precursor with, however, the opposite configuration to that of R-(xe2x88x92)-carnitine, as a by-product.
In an attempt to use the substantial amount of S-(+)-carnitine (or of a precursor, such as S-(+),-carnitinamide), which is obtained as a waste product in the industrial production of R-(xe2x88x92)-carnitine, various processes have recently been proposed based on the stereospecific synthesis of R-(xe2x88x92)-carnitine starting from achiral derivatives (crotonobetaine or gamma-butyrobetaine) obtained precisely from this S-(+)-carnitine waste product.
These processes are generally based on the stereospecific hydration of crotonobetaine and differ from one another mainly in the particular micro-organism used to produce the biotransformation. See, for example, the processes described in: EP 0 121 444 (HAMARI), EP 0 122 794 (AJINOMOTO), EP 0 148 132 (SIGMA-TAU), JP 275689/87 (BIORU), JP 61067494 (SEITETSU), JP 61234794 (SEITETSU), JP 61234788 (SEITETSU), JP 61271996 (SEITETSU), JP 61271995 (SEITETSU), EP 0 410 430 (LONZA), EP 0 195 944 (LONZA), EP 0 158 194 (LONZA), EP 0 457 735 (SIGMA-TAU).
JP 62044189 (SEITETSU) describes a process for the stereoselective production of R-(xe2x88x92)-carnitine, starting, instead, from gamma-butyrobetaine, which in turn is obtained from crotonobetaine by an enzymatic method.
All these processes present drawbacks and are pose major technical problems.
In the first place, S-(+)-carnitine has to be converted to the achiral compound (crotonobetaine or gamma-butyrobetaine) which constitutes the starting product in all the aforementioned microbiological processes.
The latter present one or more of the following problems in production on an industrial scale:
(i) the R-(xe2x88x92)-carnitine yield is extremely low;
(ii) the micro-organisms must be grown on expensive nutrient media;
(iii) the micro-organisms support only low concentrations of crotonobetaine (up to 2-3% (w/v));
(iv) collateral reactions occur, such as, in the case of the use of crotonobetaine, for instance, the reduction of the latter to gamma-butyrobetaine, or the oxidation of R-(xe2x88x92)-carnitine to 3-dehydrocarnitine, which diminish the final R-(xe2x88x92)-carnitine yield.
More recently, a chemical process has been described (U.S. Pat. Nos. 5,412,113; 5,599,978; EP 0 609 643) based on the conversion to R-(xe2x88x92)-carnitine of a starting compound containing one asymmetric carbon atom with the opposite configuration to that of R-(xe2x88x92)-carnitine, without this compound having first to be converted to the achiral intermediate, crotonobetaine or gamma-butyrobetaine, and this achiral intermediate having to be later converted to R-(xe2x88x92)-carnitine. The starting compound consists in S-(+)-carnitinamide, which, as mentioned above, is obtained as a redundant waste product in the resolution of the R,S-carnitinamide racemic mixture by means of, for instance, D-camphoric acid. According to this process, the S-(+)-carnitinamide is converted to S-(+)-carnitine; the latter is esterified to protect the carboxyl group; the ester is acylated, preferably mesylated; after restoring the carboxyl group, the acyl derivative thus obtained is converted to a chiral lactone presenting the desired R configuration, which, through basic hydrolysis, supplies the R-(xe2x88x92)-carnitine.
It should be noted that both in the microbiological processes that obtain R-(xe2x88x92)-carnitine via an achiral intermediate and in the chemical process that enables R-(xe2x88x92)-carnitine to be obtained via chiral lactone, the starting product is a precursor of carnitine with the opposite configuration to that of the R form normally obtained by resolution of racemic mixtures, e.g. from R,S carnitinamide.
In other words, the basic assumption underlying all the above-mentioned, more recent processes is that to obtain R-(xe2x88x92)-carnitine it is above all necessary to continue using the chemical process consisting in resolution of R,S racemic mixtures, since it is this that produces, as a waste product, the carnitine precursor with the opposite configuration to that of the R form, which in the most up-to-date processes is precisely what constitutes the starting product. It certainly borders on the paradoxical that the most recent, technologically advanced processes for the production of R-(xe2x88x92)-carnitine should, for the purposes of their supply of starting products, continue to have to use the oldest process for the industrial production of R-(xe2x88x92)-carnitine.
The aim of the invention described herein is to provide a chemical process for the production of R-(xe2x88x92)-carnitine that does not start from a carnitine precursor with the opposite configuration to that of the R form, such as S-(+)-carnitinamide or S-(+)-carnitine.
In particular, the aim of the invention described herein is to provide a process for the production of R-(xe2x88x92)-carnitine which does without the continued use of processes based on the resolution of racemic mixtures of carnitine precursors, without which the starting compound for the above-mentioned, more recent processes would not be available.
It is also the aim of the invention described herein to provide a chemical process for the stereoselective synthesis of R-(xe2x88x92)-carnitine, the starting material of which is a simple achiral compound, which is easy to obtain at low cost, consisting in glycerol.